Unveiling Myelodysplastic Syndromes: Exploring Pathogenic Mechanisms and Therapeutic Advances
Simple Summary
Abstract
1. Introduction
2. Pathogenesis of Myelodysplastic Syndromes
2.1. Acquisition of Somatic Driver Mutations
2.2. Common Gene Mutations in MDS Organized by Pathways
2.2.1. Epigenetic Regulation
2.2.2. RNA Splicing Machinery
2.2.3. Transcriptional Regulation and Genome Surveillance
2.2.4. Genome Stability and Chromosomal Integrity
2.3. Dysfunctional Immune System
3. Classification Systems
3.1. Current Classification Systems
3.2. Implications for Clinical Practice
4. Diagnosis and Management: Implications for Clinical Practice
4.1. Clinical Features
4.2. Evaluation and Diagnosis
4.3. Prognostic Factors
5. Treatment of MDS
5.1. Overview of Treatment
5.2. LR-MDS
5.3. HR-MDS
5.4. Emerging Therapies in MDS
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Várkonyi, J. The Myelodysplastic Syndromes; Springer Science & Business Media: Berlin, Germany, 2011; 2900p. [Google Scholar]
- Aakash, F.; Gisriel, S.D.; Zeidan, A.M.; Bennett, J.M.; Bejar, R.; Bewersdorf, J.P.; Borate, U.M.; Boultwood, J.; Brunner, A.M.; Buckstein, R.; et al. Contemporary Approach to The Diagnosis and Classification of Myelodysplastic Neoplasms/Syndromes- Recommendations from The International Consortium for MDS (icMDS). Mod. Pathol. 2024, 37, 100615. [Google Scholar] [CrossRef] [PubMed]
- Bejar, R. Clinical and genetic predictors of prognosis in myelodysplastic syndromes. Haematologica 2014, 99, 956–964. [Google Scholar] [CrossRef] [PubMed]
- Arber, D.A.; Orazi, A.; Hasserjian, R.; Thiele, J.; Borowitz, M.J.; Le Beau, M.M.; Bloomfield, C.D.; Cazzola, M.; Vardiman, J.W. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016, 127, 2391–2405. [Google Scholar] [CrossRef]
- Bănescu, C.; Tripon, F.; Muntean, C. The Genetic Landscape of Myelodysplastic Neoplasm Progression to Acute Myeloid Leukemia. Int. J. Mol. Sci. 2023, 24, 5734. [Google Scholar] [CrossRef] [PubMed]
- Vardiman, J.W. The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues: An overview with emphasis on the myeloid neoplasms. Chem. Biol. Interact. 2010, 184, 16–20. [Google Scholar] [CrossRef] [PubMed]
- Arber, D.A.; Orazi, A.; Hasserjian, R.P.; Borowitz, M.J.; Calvo, K.R.; Kvasnicka, H.M.; Wang, S.A.; Bagg, A.; Barbui, T.; Branford, S.; et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: Integrating morphologic, clinical, and genomic data. Blood J. Am. Soc. Hematol. 2022, 140, 1200–1228. [Google Scholar] [CrossRef] [PubMed]
- Döhner, H.; Weisdorf, D.J.; Bloomfield, C.D. Acute Myeloid Leukemia. N. Engl. J. Med. 2015, 373, 1136–1152. [Google Scholar] [CrossRef] [PubMed]
- Saygin, C.; Carraway, H.E. Current and emerging strategies for management of myelodysplastic syndromes. Blood Rev. 2021, 48, 100791. [Google Scholar] [CrossRef] [PubMed]
- Schuler, U. Quality of life in patients with myelodysplastic syndromes. Cancer Treat. Rev. 2007, 33, S59–S63. [Google Scholar] [CrossRef]
- Barreyro, L.; Chlon, T.M.; Starczynowski, D.T. Chronic immune response dysregulation in MDS pathogenesis. Blood 2018, 132, 1553–1560. [Google Scholar] [CrossRef]
- Zeidan, A.M.; Shallis, R.M.; Wang, R.; Davidoff, A.; Ma, X. Epidemiology of myelodysplastic syndromes: Why characterizing the beast is a prerequisite to taming it. Blood Rev. 2019, 34, 1–15. [Google Scholar] [CrossRef] [PubMed]
- Iwanaga, M.; Hsu, W.-L.; Soda, M.; Takasaki, Y.; Tawara, M.; Joh, T.; Amenomori, T.; Yamamura, M.; Yoshida, Y.; Koba, T.; et al. Risk of myelodysplastic syndromes in people exposed to ionizing radiation: A retrospective cohort study of Nagasaki atomic bomb survivors. J. Clin. Oncol. 2011, 29, 428–434. [Google Scholar] [CrossRef]
- Shallis, R.M.; Gore, S.D. Agent Orange and dioxin-induced myeloid leukemia: A weaponized vehicle of leukemogenesis. Leuk. Lymphoma 2022, 63, 1534–1543. [Google Scholar] [CrossRef]
- Haase, D. Cytogenetic features in myelodysplastic syndromes. Ann. Hematol. 2008, 87, 515–526. [Google Scholar] [CrossRef] [PubMed]
- Shahjahani, M.; Hadad, E.H.; Azizidoost, S.; Nezhad, K.C.; Shahrabi, S. Complex karyotype in myelodysplastic syndromes: Diagnostic procedure and prognostic susceptibility. Oncol. Rev. 2019, 13, 389. [Google Scholar] [CrossRef] [PubMed]
- Velegraki, M.; Stiff, A.; Papadaki, H.A.; Li, Z. Myeloid-Derived Suppressor Cells: New Insights into the Pathogenesis and Therapy of MDS. J. Clin. Med. Res. 2022, 11, 4908. [Google Scholar] [CrossRef]
- Chattopadhyaya, S.; Ghosal, S. DNA methylation: A saga of genome maintenance in hematological perspective. Hum Cell 2022, 35, 448–461. [Google Scholar] [CrossRef] [PubMed]
- Quivoron, C.; Couronné, L.; Della Valle, V.; Lopez, C.K.; Plo, I.; Wagner-Ballon, O.; Cruzeiro, M.D.; Delhommeau, F.; Arnulf, B.; Stern, M.-H.; et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 2011, 20, 25–38. [Google Scholar] [CrossRef] [PubMed]
- Fenaux, P.; Mufti, G.J.; Hellstrom-Lindberg, E.; Santini, V.; Finelli, C.; Giagounidis, A.; Schoch, R.; Gattermann, N.; Sanz, G.; List, A.; et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol. 2009, 10, 223–232. [Google Scholar] [CrossRef] [PubMed]
- Pirozzi, C.J.; Yan, H. The implications of IDH mutations for cancer development and therapy. Nat. Rev. Clin. Oncol. 2021, 18, 645–661. [Google Scholar] [CrossRef]
- Kowalczyk, A.; Zarychta, J.; Lejman, M.; Latoch, E.; Zawitkowska, J. Clinical Implications of Isocitrate Dehydrogenase Mutations and Targeted Treatment of Acute Myeloid Leukemia with Mutant Isocitrate Dehydrogenase Inhibitors-Recent Advances, Challenges and Future Prospects. Int. J. Mol. Sci. 2024, 25, 7916. [Google Scholar] [CrossRef] [PubMed]
- DiNardo, C.D.; Roboz, G.J.; Watts, J.M.; Madanat, Y.F.; Prince, G.T.; Baratam, P.; de Botton, S.; Stein, A.; Foran, J.M.; Arellano, M.L.; et al. Final phase 1 substudy results of ivosidenib for patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome. Blood Adv. 2024, 8, 4209–4220. [Google Scholar] [CrossRef] [PubMed]
- Ogawa, S. Genetics of MDS. Blood 2019, 133, 1049–1059. [Google Scholar] [CrossRef] [PubMed]
- Bersanelli, M.; Travaglino, E.; Meggendorfer, M.; Matteuzzi, T.; Mosca, E.; Chiereghin, C.; Di Nanni, N.; Gnocchi, M.; Zampini, M.; Rossi, M.; et al. Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes. J. Clin. Oncol. 2021, 39, 1223–1233. [Google Scholar] [CrossRef]
- Du, Y.; Luo, L.; Xu, X.; Yang, X.; Yang, X.; Xiong, S.; Yu, J.; Liang, T.; Guo, L. Unleashing the Power of Synthetic Lethality: Augmenting Treatment Efficacy through Synergistic Integration with Chemotherapy Drugs. Pharmaceutics 2023, 15, 2433. [Google Scholar] [CrossRef] [PubMed]
- Cumbo, C.; Tota, G.; Anelli, L.; Zagaria, A.; Specchia, G.; Albano, F. TP53 in Myelodysplastic Syndromes: Recent Biological and Clinical Findings. Int. J. Mol. Sci. 2020, 21, 3432. [Google Scholar] [CrossRef] [PubMed]
- Santini, V.; Stahl, M.; Sallman, D.A. TP53 Mutations in Acute Leukemias and Myelodysplastic Syndromes: Insights and Treatment Updates. American Society of Clinical Oncology Educational Book 2024. Available online: https://ascopubs.org/doi/10.1200/EDBK_432650 (accessed on 11 November 2024).
- Viny, A.D.; Bowman, R.L.; Liu, Y.; Lavallée, V.-P.; Eisman, S.E.; Xiao, W.; Durham, B.H.; Navitski, A.; Park, J.; Braunstein, S.; et al. Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation. Cell Stem Cell 2019, 25, 682–696.e8. [Google Scholar] [CrossRef]
- Jann, J.C.; Hergott, C.B.; Winkler, M.; Liu, Y.; Braun, B.; Charles, A.; Copson, K.M.; Barua, S.; Meggendorfer, M.; Nadarajah, N.; et al. Subunit-specific analysis of cohesin-mutant myeloid malignancies reveals distinct ontogeny and outcomes. Leukemia 2024, 38, 1992–2002. [Google Scholar] [CrossRef] [PubMed]
- Tothova, Z.; Valton, A.-L.; Gorelov, R.A.; Vallurupalli, M.; Krill-Burger, J.M.; Holmes, A.; Landers, C.C.; Haydu, J.E.; Malolepsza, E.; Hartigan, C.; et al. Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML. JCI Insight 2021, 8, e142149. [Google Scholar] [CrossRef]
- Pellagatti, A.; Cazzola, M.; Giagounidis, A.; Perry, J.; Malcovati, L.; Della Porta, M.G.; Jädersten, M.; Killick, S.; Verma, A.; Norbury, C.J.; et al. Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells. Leukemia 2010, 24, 756–764. [Google Scholar] [CrossRef]
- Kristinsson, S.Y.; Björkholm, M.; Hultcrantz, M.; Derolf, Å.R.; Landgren, O.; Goldin, L.R. Chronic immune stimulation might act as a trigger for the development of acute myeloid leukemia or myelodysplastic syndromes. J. Clin. Oncol. 2011, 29, 2897–2903. [Google Scholar] [CrossRef]
- Choudhary, G.S.; Pellagatti, A.; Agianian, B.; A Smith, M.; Bhagat, T.D.; Gordon-Mitchell, S.; Sahu, S.; Pandey, S.; Shah, N.; Aluri, S.; et al. Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations. Elife 2022, 11, e78136. [Google Scholar] [CrossRef] [PubMed]
- Garcia-Manero, G.; Winer, E.S.; DeAngelo, D.J.; Tarantolo, S.R.; Sallman, D.A.; Dugan, J.; Groepper, S.; Giagounidis, A.; Gotze, K.S.; Metzeler, K.; et al. Phase 1/2a study of the IRAK4 inhibitor CA-4948 as monotherapy or in combination with azacitidine or venetoclax in patients with relapsed/refractory (R/R) acute myeloid leukemia or lyelodysplastic syndrome. J. Clin. Oncol. 2022, 40, 7016. Available online: https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.7016 (accessed on 11 November 2024). [CrossRef]
- Bataller, A.; Montalban-Bravo, G.; Soltysiak, K.A.; Garcia-Manero, G. The role of TGFβ in hematopoiesis and myeloid disorders. Leukemia 2019, 33, 1076–1089. [Google Scholar] [CrossRef] [PubMed]
- Suragani, R.N.V.S.; Cadena, S.M.; Cawley, S.M.; Sako, D.; Mitchell, D.; Li, R.; Davies, M.V.; Alexander, M.J.; Devine, M.; Loveday, K.S.; et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat. Med. 2014, 20, 408–414. [Google Scholar] [CrossRef] [PubMed]
- Fenaux, P.; Platzbecker, U.; Mufti, G.J.; Garcia-Manero, G.; Buckstein, R.; Santini, V.; Díez-Campelo, M.; Finelli, C.; Cazzola, M.; Ilhan, O.; et al. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N. Engl. J. Med. 2020, 382, 140–151. [Google Scholar] [CrossRef] [PubMed]
- Lenhard Rudolph, K. Telomeres and Telomerase in Aging, Disease, and Cancer: Molecular Mechanisms of Adult Stem Cell Ageing; Springer Science & Business Media: Berlin, Germany, 2007; 332p. [Google Scholar]
- Briatore, F.; Barrera, G.; Pizzimenti, S.; Toaldo, C.; Della Casa, C.; Laurora, S.; Pettazzoni, P.; Dianzani, M.U.; Ferrero, D. Increase of telomerase activity and hTERT expression in myelodysplastic syndromes. Cancer Biol. Ther. 2009, 8, 883–889. [Google Scholar] [CrossRef]
- Platzbecker, U.; Santini, V.; Fenaux, P.; Sekeres, M.A.; Savona, M.R.; Madanat, Y.F.; Díez-Campelo, M.; Valcárcel, D.; Illmer, T.; Jonášová, A.; et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): A multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2024, 403, 249–260. [Google Scholar] [CrossRef] [PubMed]
- Valent, P.; Orazi, A.; Steensma, D.P.; Ebert, B.L.; Haase, D.; Malcovati, L.; van de Loosdrecht, A.A.; Haferlach, T.; Westers, T.M.; Wells, D.A.; et al. Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions. Oncotarget 2017, 8, 73483–73500. [Google Scholar] [CrossRef]
- Khoury, J.D.; Solary, E.; Abla, O.; Akkari, Y.; Alaggio, R.; Apperley, J.F.; Bejar, R.; Berti, E.; Busque, L.; Chan, J.K.C.; et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia 2022, 36, 1703–1719. [Google Scholar] [CrossRef]
- Bernard, E.; Tuechler, H.; Greenberg, P.L.; Hasserjian, R.P.; Ossa, J.E.A.; Nannya, Y.; Devlin, S.M.; Creignou, M.; Pinel, P.; Monnier, L.; et al. Molecular International Prognostic Scoring System for Myelodysplastic Syndromes. NEJM Evid. 2022, 1, EVIDoa2200008. [Google Scholar] [CrossRef] [PubMed]
- LLee, W.-H.; Lin, C.-C.; Tsai, C.-H.; Tien, F.-M.; Lo, M.-Y.; Tseng, M.-H.; Kuo, Y.-Y.; Yu, S.-C.; Liu, M.-C.; Yuan, C.-T.; et al. Comparison of the 2022 world health organization classification and international consensus classification in myelodysplastic syndromes/neoplasms. Blood Cancer J. 2024, 14, 57. [Google Scholar] [CrossRef]
- Britt, A.; Mohyuddin, G.R.; McClune, B.; Singh, A.; Lin, T.; Ganguly, S.; Abhyankar, S.; Shune, L.; McGuirk, J.; Skikne, B.; et al. Acute myeloid leukemia or myelodysplastic syndrome with chromosome 17 abnormalities and long-term outcomes with or without hematopoietic stem cell transplantation. Leuk. Res. 2020, 95, 106402. [Google Scholar] [CrossRef]
- Lindsley, R.C.; Saber, W.; Mar, B.G.; Redd, R.; Wang, T.; Haagenson, M.D.; Grauman, P.V.; Hu, Z.-H.; Spellman, S.R.; Lee, S.J.; et al. Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation. N. Engl. J. Med. 2017, 376, 536–547. [Google Scholar] [CrossRef]
- Malcovati, L.; Stevenson, K.; Papaemmanuil, E.; Neuberg, D.; Bejar, R.; Boultwood, J.; Bowen, D.T.; Campbell, P.J.; Ebert, B.L.; Fenaux, P.; et al. SF3B1-mutant MDS as a distinct disease subtype: A proposal from the International Working Group for the Prognosis of MDS. Blood 2020, 136, 157–170. [Google Scholar] [CrossRef]
- Ma, X.; Does, M.; Raza, A.; Mayne, S.T. Myelodysplastic syndromes: Incidence and survival in the United States. Cancer 2007, 109, 1536–1542. [Google Scholar] [CrossRef]
- Gurnari, C.; Piciocchi, A.; Soddu, S.; Bonanni, F.; Scalzulli, E.; Niscola, P.; Di Veroli, A.; Piccioni, A.L.; Piedimonte, M.; Maiorana, G.; et al. Myelodysplastic syndromes with del(5q): A real-life study of determinants of long-term outcomes and response to lenalidomide. Blood Cancer J. 2022, 12, 132. [Google Scholar] [CrossRef] [PubMed]
- Greenberg, P.; Cox, C.; LeBeau, M.M.; Fenaux, P.; Morel, P.; Sanz, G.; Sanz, M.; Vallespi, T.; Hamblin, T.; Oscier, D.; et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997, 89, 2079–2088. [Google Scholar] [CrossRef] [PubMed]
- Brownstein, C.G.; Daguenet, E.; Guyotat, D.; Millet, G.Y. Chronic fatigue in myelodysplastic syndromes: Looking beyond anemia. Crit. Rev. Oncol. Hematol. 2020, 154, 103067. [Google Scholar] [CrossRef] [PubMed]
- Grignano, E.; Jachiet, V.; Fenaux, P.; Ades, L.; Fain, O.; Mekinian, A. Autoimmune manifestations associated with myelodysplastic syndromes. Ann. Hematol. 2018, 97, 2015–2023. [Google Scholar] [CrossRef]
- Greenberg, P.L.; Tuechler, H.; Schanz, J.; Sanz, G.; Garcia-Manero, G.; Solé, F.; Bennett, J.M.; Bowen, D.; Fenaux, P.; Dreyfus, F.; et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012, 120, 2454–2465. [Google Scholar] [CrossRef]
- Turner, J.; Parsi, M.; Badireddy, M. Anemia. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2024. Available online: http://www.ncbi.nlm.nih.gov/books/NBK499994/ (accessed on 29 September 2024).
- Shetty, V.T.; Mundle, S.D.; Raza, A. Pseudo Pelger-Huët anomaly in myelodysplastic syndrome: Hyposegmented apoptotic neutrophil? Blood 2001, 98, 1273–1275. [Google Scholar] [CrossRef] [PubMed]
- Schanz, J.; Tüchler, H.; Solé, F.; Mallo, M.; Luño, E.; Cervera, J.; Granada, I.; Hildebrandt, B.; Slovak, M.L.; Ohyashiki, K.; et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J. Clin. Oncol. 2012, 30, 820–829. [Google Scholar] [CrossRef]
- Thol, F.; Platzbecker, U. Do next-generation sequencing results drive diagnostic and therapeutic decisions in MDS? Blood Adv. 2019, 3, 3449–3453. [Google Scholar] [CrossRef] [PubMed]
- Naqvi, K.; Garcia-Manero, G.; Sardesai, S.; Oh, J.; Vigil, C.E.; Pierce, S.; Lei, X.; Shan, J.; Kantarjian, H.M.; Suarez-Almazor, M.E. Association of comorbidities with overall survival in myelodysplastic syndrome: Development of a prognostic model. J. Clin. Oncol. 2011, 29, 2240–2246. [Google Scholar] [CrossRef] [PubMed]
- Kuendgen, A.; Strupp, C.; Aivado, M.; Hildebrandt, B.; Haas, R.; Gattermann, N.; Germing, U. Myelodysplastic syndromes in patients younger than age 50. J. Clin. Oncol. 2006, 24, 5358–5365. [Google Scholar] [CrossRef]
- Kantarjian, H.; O’Brien, S.; Ravandi, F.; Cortes, J.; Shan, J.; Bennett, J.M.; List, A.; Fenaux, P.; Sanz, G.; Issa, J.-P.; et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System. Cancer 2008, 113, 1351–1361. [Google Scholar] [CrossRef] [PubMed]
- Aul, C.; Gattermann, N.; Heyll, A.; Germing, U.; Derigs, G.; Schneider, W. Primary myelodysplastic syndromes: Analysis of prognostic factors in 235 patients and proposals for an improved scoring system. Leukemia 1992, 6, 52–59. [Google Scholar] [PubMed]
- Balducci, L. Transfusion independence in patients with myelodysplastic syndromes: Impact on outcomes and quality of life. Cancer 2006, 106, 2087–2094. [Google Scholar] [CrossRef]
- Haferlach, T.; Nagata, Y.; Grossmann, V.; Okuno, Y.; Bacher, U.; Nagae, G.; Schnittger, S.; Sanada, M.; Kon, A.; Alpermann, T.; et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014, 28, 241–247. [Google Scholar] [CrossRef]
- Sanz, G.F.; Sanz, M.A.; Vallespí, T.; Cañizo, M.C.; Torrabadella, M.; García, S.; Irriguible, D.; San Miguel, J. Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: A multivariate analysis of prognostic factors in 370 patients. Blood 1989, 74, 395–408. [Google Scholar] [CrossRef]
- Platzbecker, U.; Symeonidis, A.; Oliva, E.N.; Goede, J.S.; Delforge, M.; Mayer, J.; Slama, B.; Badre, S.; Gasal, E.; Mehta, B.; et al. A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia 2017, 31, 1944–1950. [Google Scholar] [CrossRef]
- Greenberg, P.L.; Sun, Z.; Miller, K.B.; Bennett, J.M.; Tallman, M.S.; Dewald, G.; Paietta, E.; van der Jagt, R.; Houston, J.; Thomas, M.L.; et al. Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: Results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology Group (E1996). Blood 2009, 114, 2393–2400. [Google Scholar] [CrossRef] [PubMed]
- Jädersten, M.; Malcovati, L.; Dybedal, I.; Della Porta, M.G.; Invernizzi, R.; Montgomery, S.M.; Pascutto, C.; Porwit, A.; Cazzola, M.; Hellstro-Lindberg, E. Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J. Clin. Oncol. 2008, 26, 3607–3613. [Google Scholar] [CrossRef] [PubMed]
- Platzbecker, U.; Della Porta, M.G.; Santini, V.; Zeidan, A.M.; Komrokji, R.S.; Shortt, J.; Valcarcel, D.; Jonasova, A.; Dimicoli-Salazar, S.; Tiong, I.S.; et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): Interim analysis of a phase 3, open-label, randomised controlled trial. Lancet 2023, 402, 373–385. [Google Scholar] [CrossRef]
- Jabbour, E.; Short, N.J.; Montalban-Bravo, G.; Huang, X.; Bueso-Ramos, C.; Qiao, W.; Yang, H.; Zhao, C.; Kadia, T.; Borthakur, G.; et al. Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood 2017, 130, 1514–1522. [Google Scholar] [CrossRef] [PubMed]
- Savona, M.R.; Odenike, O.; Amrein, P.C.; Steensma, D.P.; DeZern, A.E.; Michaelis, L.C.; Faderl, S.; Harb, W.; Kantarjian, H.; Lowder, J.; et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: A multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019, 6, e194–e203. [Google Scholar] [CrossRef]
- Nakamura, R.; Saber, W.; Martens, M.J.; Ramirez, A.; Scott, B.; Oran, B.; Leifer, E.; Tamari, R.; Mishra, A.; Maziarz, R.T.; et al. Biologic Assignment Trial of Reduced-Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients 50-75 Years of Age With Advanced Myelodysplastic Syndrome. J. Clin. Oncol. 2021, 39, 3328–3339. [Google Scholar] [CrossRef]
- Platzbecker, U.; Schetelig, J.; Finke, J.; Trenschel, R.; Scott, B.L.; Kobbe, G.; Schaefer-Eckart, K.; Bornhäuser, M.; Itzykson, R.; Germing, U.; et al. Allogeneic hematopoietic cell transplantation in patients age 60-70 years with de novo high-risk myelodysplastic syndrome or secondary acute myelogenous leukemia: Comparison with patients lacking donors who received azacitidine. Biol. Blood Marrow Transplant. 2012, 18, 1415–1421. [Google Scholar] [CrossRef] [PubMed]
- Scott, B.L.; Pasquini, M.C.; Logan, B.R.; Wu, J.; Devine, S.M.; Porter, D.L.; Maziarz, R.T.; Warlick, E.D.; Fernandez, H.F.; Alyea, E.P.; et al. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J. Clin. Oncol. 2017, 35, 1154–1161. [Google Scholar] [CrossRef] [PubMed]
- Martino, R.; Iacobelli, S.; Brand, R.; Jansen, T.; van Biezen, A.; Finke, J.; Bacigalupo, A.; Beelen, D.; Reiffers, J.; Devergie, A.L.; et al. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 2006, 108, 836–846. [Google Scholar] [CrossRef] [PubMed]
- Alyea, E.P.; Kim, H.T.; Ho, V.; Cutler, C.; Gribben, J.; DeAngelo, D.J.; Lee, S.J.; Windawi, S.; Ritz, J.; Stone, R.M.; et al. Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood 2005, 105, 1810–1814. [Google Scholar] [CrossRef]
- Lübbert, M.; Suciu, S.; Baila, L.; Rüter, B.H.; Platzbecker, U.; Giagounidis, A.; Selleslag, D.; Labar, B.; Germing, U.; Salih, H.R.; et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: Final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J. Clin. Oncol. 2011, 29, 1987–1996. [Google Scholar] [PubMed]
- Kantarjian, H.M.; O’Brien, S.; Shan, J.; Aribi, A.; Garcia-Manero, G.; Jabbour, E.; Ravandi, F.; Cortes, J.; Davisson, J.; Issa, J. Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome. Cancer 2007, 109, 265–273. [Google Scholar] [CrossRef]
- Lee, P.; Yim, R.; Yung, Y.; Chu, H.T.; Yip, P.K.; Gill, H. Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome. Int. J. Mol. Sci. 2021, 22, 10232. [Google Scholar] [CrossRef]
- 319 Efficacy and Safety of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Treatment-Naive, Higher-Risk Myelodysplastic Syndromes. 2023. Available online: https://ash.confex.com/ash/2023/webprogram/Paper189446.html (accessed on 11 November 2024).
- Zeidan, A.M.; Borate, U.; Pollyea, D.A.; Brunner, A.M.; Roncolato, F.; Garcia, J.S.; Filshie, R.; Odenike, O.; Watson, A.M.; Krishnadasan, R.; et al. A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Am. J. Hematol. 2023, 98, 272–281. [Google Scholar] [CrossRef]
- Bataller, A.; Montalban-Bravo, G.; Bazinet, A.; Alvarado, Y.; Chien, K.; Venugopal, S.; Ishizawa, J.; Hammond, D.; Swaminathan, M.; Sasaki, K.; et al. Oral decitabine plus cedazuridine and venetoclax in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: A single-centre, phase 1/2 study. Lancet Haematol. 2024, 11, e186–e195. [Google Scholar] [CrossRef] [PubMed]
- Garcia, J.S.; Kim, H.T.; Murdock, H.M.; Ansuinelli, M.; Brock, J.; Cutler, C.S.; Gooptu, M.; Ho, V.T.; Koreth, J.; Nikiforow, S.; et al. Prophylactic maintenance with venetoclax/azacitidine after reduced-intensity conditioning allogeneic transplant for high-risk MDS and AML. Blood Adv. 2024, 8, 978–990. [Google Scholar] [CrossRef] [PubMed]
- Peterlin, P.; Le Bris, Y.; Turlure, P.; Chevallier, P.; Ménard, A.; Gourin, M.-P.; Dumas, P.-Y.; Thepot, S.; Berceanu, A.; Park, S.; et al. CPX-351 in higher risk myelodysplastic syndrome and chronic myelomonocytic leukaemia: A multicentre, single-arm, phase 2 study. Lancet Haematol. 2023, 10, e521–e529. [Google Scholar] [CrossRef]
- Othman, J.; Wilhelm-Benartzi, C.; Dillon, R.; Knapper, S.; Freeman, S.D.; Batten, L.M.; Canham, J.; Hinson, E.L.; Wych, J.; Betteridge, S.; et al. A randomized comparison of CPX-351 and FLAG-Ida in adverse karyotype AML and high-risk MDS: The UK NCRI AML19 trial. Blood Adv. 2023, 7, 4539–4549. [Google Scholar] [CrossRef]
- Montalban-Bravo, G.; Jabbour, E.; Borthakur, G.; Kadia, T.; Ravandi, F.; Chien, K.; Pemmaraju, N.; Hammond, D.; Dong, X.Q.; Schneider, H.; et al. Phase 1/2 study of CPX-351 for patients with Int-2 or high risk International Prognostic Scoring System myelodysplastic syndromes and chronic myelomonocytic leukaemia after failure to hypomethylating agents. Br. J. Haematol. 2024, 204, 898–909. [Google Scholar] [CrossRef] [PubMed]
- Sekeres, M.A.; Watts, J.; Radinoff, A.; Sangerman, M.A.; Cerrano, M.; Lopez, P.F.; Zeidner, J.F.; Campelo, M.D.; Graux, C.; Liesveld, J.; et al. Randomized phase 2 trial of pevonedistat plus azacitidine versus azacitidine for higher-risk MDS/CMML or low-blast AML. Leukemia 2021, 35, 2119–2124. [Google Scholar] [CrossRef] [PubMed]
- Adès, L.; Girshova, L.; Doronin, V.A.; Díez-Campelo, M.; Valcárcel, D.; Kambhampati, S.; Viniou, N.-A.; Woszczyk, D.; Arias, R.D.P.; Symeonidis, A.; et al. Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML. Blood Adv. 2022, 6, 5132–5145. [Google Scholar] [CrossRef]
- Short, N.J.; Muftuoglu, M.; Ong, F.; Nasr, L.; Macaron, W.; Montalban-Bravo, G.; Alvarado, Y.; Basyal, M.; Daver, N.; Dinardo, C.D.; et al. A phase 1/2 study of azacitidine, venetoclax and pevonedistat in newly diagnosed secondary AML and in MDS or CMML after failure of hypomethylating agents. J. Hematol. Oncol. 2023, 16, 73. [Google Scholar] [CrossRef]
- Watts, J.M.; Baer, M.R.; Yang, J.; Prebet, T.; Lee, S.; Schiller, G.J.; Dinner, S.N.; Pigneux, A.; Montesinos, P.; Wang, E.S.; et al. Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: Phase 1 results of a phase 1/2 trial. Lancet Haematol. 2023, 10, e46–e58. [Google Scholar] [CrossRef] [PubMed]
- DiNardo, C.D.; Venugopal, S.; Lachowiez, C.; Takahashi, K.; Loghavi, S.; Montalban-Bravo, G.; Wang, X.; Carraway, H.; Sekeres, M.; Sukkur, A.; et al. Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome. Blood Adv. 2023, 7, 2378–2387. [Google Scholar] [CrossRef] [PubMed]
- Chien, K.S.; Kim, K.; Nogueras-Gonzalez, G.M.; Borthakur, G.; Naqvi, K.; Daver, N.G.; Montalban-Bravo, G.; Cortes, J.E.; DiNardo, C.D.; Jabbour, E.; et al. Phase II study of azacitidine with pembrolizumab in patients with intermediate-1 or higher-risk myelodysplastic syndrome. Br. J. Haematol. 2021, 195, 378–387. [Google Scholar] [CrossRef]
- Assouline, S.; Michaelis, L.C.; Othus, M.; Hay, A.E.; Walter, R.B.; Jacoby, M.A.; Schroeder, M.A.; Uy, G.L.; Law, L.Y.; Cheema, F.; et al. A randomized phase II/III study of “novel therapeutics” versus azacitidine in newly diagnosed patients with acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML), age 60 or older: A report of the comparison of azacitidine and nivolumab to azacitidine: SWOG S1612. Leuk. Lymphoma 2023, 64, 473–477. [Google Scholar] [PubMed]
- Gerds, A.T.; Scott, B.L.; Greenberg, P.; Lin, T.L.; Pollyea, D.A.; Verma, A.; Dail, M.; Feng, Y.; Green, C.; Ma, C.; et al. Atezolizumab alone or in combination did not demonstrate a favorable risk-benefit profile in myelodysplastic syndrome. Blood Adv. 2022, 6, 1152–1161. [Google Scholar] [CrossRef] [PubMed]
- O’Connell, C.L.; Baer, M.R.; Ørskov, A.D.; Saini, S.K.; Duong, V.H.; Kropf, P.; Hansen, J.W.; Tsao-Wei, D.; Jang, H.S.; Emadi, A.; et al. Safety, Outcomes, and T-Cell Characteristics in Patients with Relapsed or Refractory MDS or CMML Treated with Atezolizumab in Combination with Guadecitabine. Clin. Cancer Res. 2022, 28, 5306–5316. [Google Scholar] [CrossRef] [PubMed]
Overexpressed | Downregulated |
---|---|
|
|
WHO Fifth Edition | ICC |
---|---|
CHIP | CHIP |
CCUS | CCUS |
MDS with LB and SF3B1 mutation | MDS with mutated SF3B1 |
MDS with LB and RS (acceptable alternative terminology) | Not included |
MDS with LB and isolated 5q deletion | MDS with del(5q) |
MDS with LB | MDS-NOS with SLD |
MDS with LB | MDS-NOS with MLD |
Not include | MDS-NOS without dysplasia |
MDS, hypoplastic | Not included |
MDS with IB1 | MDS with EB |
MDS with IB2 | MDS/AML |
MDS with increased blasts and fibrosis | Not included |
MDS with bi-allelic TP53 inactivation | MDS and MDS/AML with mutated TP53 |
Classification | IPSS | IPSS-R | IPSS-M |
---|---|---|---|
Key Parameters | - Cytogenetics (Good, Intermediate, Poor) - Bone marrow blast percentage - Hemoglobin - Platelet count | - Cytogenetics (refined into 5 risk groups) - Bone marrow blast percentage - Hemoglobin - Platelet count - Absolute neutrophil count (ANC) | - Molecular mutations (31 genes) - Cytogenetics (integrated with molecular findings) - Bone marrow blast percentage - Hemoglobin, platelet, and ANC counts |
Cytogenetic Risk Categories | 3 risk groups (Good, Intermediate, Poor) | 5 risk groups (Very good, Good, Intermediate, Poor, Very poor) | Integrated molecular and cytogenetic risk profiles |
Blast Thresholds | <5%, 5–10%, 11–20%, and 21–30% | <2%, 2–5%, 5–10%, >10% | Similar to IPSS-R |
Prognostic Groups | - Low-risk: 0–1 - Intermediate-1: 1.5–2 - Intermediate-2: 2.5–3.5 - High risk: ≥4 | - Very low: ≤1.5 - Low: >1.5–3 - Intermediate: >3–4.5 - High: >4.5–6 - Very high: >6 | - Very Low: ≤1.5 - Low: >1.5–3 - Moderate Low: >3–4 - Moderate–High: >4–6 - High: >6–8 - Very High: >8 |
Criteria | Indications |
---|---|
Risk Stratification | - IPSS-R or IPSS-M: High or very high risk scores. |
Disease Characteristics | - High blast count: >10% blasts in bone marrow or >5% blasts in peripheral blood. - Cytogenetic abnormalities: complex karyotypes (e.g., monosomy 7, del(5q), del(7q)) or high-risk chromosomal changes. - Failure of hypomethylating agents (azacitidine/decitabine). |
Age and Performance Status | Younger age (60–70 years) and ECOG performance status 0–1. |
Treatment/Trial | Phase | Population | Results | Toxicities (Grade ≥ 3) |
---|---|---|---|---|
Venetoclax + Azacitidine in HR-MDS | 1b/2 | Treatment-naïve HR-MDS patients | Median follow-up of 31.9 months, 29.9% CR rate, with median OS of 26 months | Neutropenia (48.6%), thrombocytopenia (43%), febrile neutropenia (42.1%), anemia (34.6%), and infections (57%) |
Venetoclax + Azacitidine in Relapsed/Refractory HR-MDS | 1b | Relapsed/refractory HR-MDS after HMA failure | Median follow-up of 21.2 months. Median OS 12.6 months, 7% CR, 32% mCR | Febrile neutropenia (34%), thrombocytopenia (32%) |
Decitabine-Cedazuridine + Venetoclax | 1/2 | Treatment-naïve HR-MDS and CMML | Median follow-up of 10.8 months, 95% ORR, and 49% proceeded to transplant | Thrombocytopenia (85%), neutropenia (74%), and febrile neutropenia (21%) |
CPX-351 in HR-MDS/CMML | 2 | Treatment-naïve HR-MDS or CMML | Median follow-up of 16.1 months, 87% ORR, and 94% proceeded to transplant | Pulmonary (26%) and cardiovascular (19%) |
CPX-351 vs. FLAG-Ida in HR-MDS (UK NCRI AML19 Trial) | 3 | Younger adults with high-risk MDS or adverse cytogenetic AML | ORR: 64% and 76%. Median OS: 13.3 vs. 11.4. Median RFS: 22.1 vs. 8.35 | Non-hematological toxicities: 18% vs. 21% |
CPX-351 | 1/2 | HR-MDS or CMML after failure of HMA | ORR: 56%. Median OS: 8.7 months. Median RFS: 9.2 months | Febrile neutropenia (48%) and lung infection (20%) |
Pevonedistat + Azacitidine vs. Azacitidine in HR-MDS/CMML/Low blast AML | 2 | Treatment-naïve HR-MDS or CMML or low blast AML | Median fu: 21.4 and 19 months. ORR: 70.9% and 60.4%. Median OS: 21.8 vs. 19 m. Median RFS: 21 vs. 16.6m | Neutropenia (33% vs. 27%), febrile neutropenia (26% vs. 29%), anemia (19% vs. 27%), and thrombocytopenia (19% vs. 23%) |
Pevonedistat + Azacitidine vs. Azacitidine | 3 | Treatment-naïve HR-MDS or CMML or AML | Median EFS in the HR MDS cohort was 19.2 vs. 15.6 months. Median OS was 21.6 vs. 17.5 months | Anemia (33% vs. 34%), neutropenia (31% vs. 33%), and thrombocytopenia (30% vs. 30%) |
Pevonedistat + Azacitidine + Venetoclax | 1/2 | HR-MDS or CMML or secondary AML after failure of HMA | In MDS/CMML cohort, ORR: 75%, CR: 13% | Infection (35%), febrile neutropenia (25%), hypophosphatemia (23%) |
Ivosidenib in IDH1-Mutant MDS | 1 | Relapsed/refractory MDS with mutant IDH-1 | ORR: 83% CR: 39% Median OS: 35.7m | Grade 1 QT interval prolongation (5.3%) and Grade 2 differentiation syndrome (10.5%) |
Olutasidenib in IDH-1 Mutant AML/MDS | 1/2 | Monotherapy: 6 patients. Combination with Azacitidine: 7 patients | Monotherapy: ORR: 33%, CR: 17%. Combination with Azacitidine ORR: 86%, CR: 57% | Monotherapy: thrombocytopenia (28%), febrile neutropenia (22%), and anemia (22%) Combination therapy: thrombocytopenia (19%), febrile neutropenia (13%), neutropenia (13%), and anemia (20%) |
Enasidenib in IDH-2-mutated MDS patients | 1 | Monotherapy: 23 patients with prior HMA failure. Combination with Azacitidine: 27 patients newly diagnosed | Monotherapy: ORR: 35%, mOS: 20 m. Combination with Azacitidine ORR: 74%, mOS: 26 m | Neutropenia (40%), nausea (36%), constipation (32%), and fatigue (26%) |
Pembrolizumab + Azacitidine in HR-MDS | 2 | Untreated HR-MDS: 17 patients. Prior HMA failure: 20 patients |
Untreated: ORR:76% CR: 18% mOS: NR Prior HMA: ORR:25% CR: 5% mOS:5.8 m | Pneumonia (32%), arthralgias (24%), and constipation (24%) |
Nivolumab in HR-MDS/AML | 2/3 | 12 MDS patients. Azacitidine (6) vs. Nivolumab + Azacitidine (6) | mOS: 6.9m vs. 5.2 m | Early deaths were higher in the combination group (24% vs. 4%), leading to early trial closure |
Atezolizumab + Guadecitabine in R/R HR-MDS/CMML | 1/2 | 30 MDS patients relapsed or refractory to HMA |
ORR: 33% CR: 6% mOS: 16.4m | Deaths ≤ 30 days (9%); immune-related adverse events (IRAEs) occurred in 36% of patients |
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Thalambedu, N.; Mohan Lal, B.; Harbaugh, B.; Alapat, D.V.; Gaddam, M.; Gentille Sanchez, C.G.; Kumaran, M.; Varma, A. Unveiling Myelodysplastic Syndromes: Exploring Pathogenic Mechanisms and Therapeutic Advances. Cancers 2025, 17, 508. https://doi.org/10.3390/cancers17030508
Thalambedu N, Mohan Lal B, Harbaugh B, Alapat DV, Gaddam M, Gentille Sanchez CG, Kumaran M, Varma A. Unveiling Myelodysplastic Syndromes: Exploring Pathogenic Mechanisms and Therapeutic Advances. Cancers. 2025; 17(3):508. https://doi.org/10.3390/cancers17030508
Chicago/Turabian StyleThalambedu, Nishanth, Bhavesh Mohan Lal, Brent Harbaugh, Daisy V. Alapat, Mamatha Gaddam, Cesar Giancarlo Gentille Sanchez, Muthu Kumaran, and Ankur Varma. 2025. "Unveiling Myelodysplastic Syndromes: Exploring Pathogenic Mechanisms and Therapeutic Advances" Cancers 17, no. 3: 508. https://doi.org/10.3390/cancers17030508
APA StyleThalambedu, N., Mohan Lal, B., Harbaugh, B., Alapat, D. V., Gaddam, M., Gentille Sanchez, C. G., Kumaran, M., & Varma, A. (2025). Unveiling Myelodysplastic Syndromes: Exploring Pathogenic Mechanisms and Therapeutic Advances. Cancers, 17(3), 508. https://doi.org/10.3390/cancers17030508